CZ25296A3 - Derivative of 4-aminobenzoylguanidine being substituted in ortho position, process of its preparation and pharmaceutical composition containing thereof - Google Patents

Abstract

2-Alkyl-4-amino-5-alkylsulphonylbenzoylguanidine derivs. of formula (I) and their salts are new: R<1>=A, CF3, CH2F, CHF2 or C2F5; R<2>,R<3>=H, A, 3-7C cycloalkyl, Ph' or Het; or R<2>+R<3>=4-5C alkylene; Het=N- or C-bonded, mono- or bicyclic, satd., unsatd. or aromatic heterocycle, contg. 1-4 of N, O and S, opt. substd. by 1-3 of Hal, CF3, A, OH, OA, SH, SA, NH2, NHA, NA2, CN, NO2 and/or carbonyl O; A=1-6C alkyl; Hal=F, Cl, Br or I; Ph'=phenyl, opt. substd. by 1-3 of A, OA, F, Cl, Br and/or CF3.

Description

Technical field

The present invention relates to an ortho-substituted 4-aminobenzoylguanidine derivative which is well tolerated and has valuable properties such that it is suitable for the manufacture of pharmaceutical compositions or as an intermediate for the manufacture of other pharmaceutically active substances. The invention also relates to a process for its preparation and to a pharmaceutical composition containing it.

BACKGROUND OF THE INVENTION

The best known active ingredient of the acylguanidines group is amiloride. However, this substance exhibits primarily a blood pressure lowering and saluretic effect, which is undesirable in the treatment of cardiac rhythm disturbances, while the antiarrhythmic characteristics are only slightly emphasized.

Structurally similar are the compounds known, for example, from European Patent Publication No. 04 16 499.

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds with valuable properties, in particular compounds which can be used for the manufacture of medicaments or as intermediates for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention provides a novel ortho-substituted 4-aminobenzoylguanidine derivative of the formula I

Where is it

R ¹ radical A, CF, CH2F, CHF2, C2F5,

R ² and R ³ are each independently hydrogen, A, C 3 -C 7 cycloalkyl, Ph or Het, or taken together with an alkylene group of 4 or 5 carbon atoms,

Het a mononuclear or bi-core, saturated, unsaturated or aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and / or sulfur atoms bonded via a nitrogen or carbon atom, optionally substituted by one, two or three substituents selected from halogen, trifluoromethyl, A, hydroxy, OA, SH, SA, NH 2, NHA, NA 2, cyano, nitro and / or carbonyl oxygen,

A (C1-C6) alkyl,

Hal is fluorine, chlorine, bromine or iodine;

A phenyl group optionally substituted by one, two or three substituents selected from the group consisting of A, OA, NH 2, NHA, NA 2, fluorine, chlorine, bromine and trifluoromethyl, and pharmaceutically acceptable salts thereof.

Indeed, it has been found that the novel compounds of the formula I and their physiologically acceptable salts, with good tolerability, have valuable pharmacological properties.

The novel compounds of formula (I) according to the invention are inhibitors of cellular Na ⁺ / H ⁺ antiporters, i.e., active substances that inhibit the mechanism of Na ⁺ / H ⁺ exchange in cells (Dusing et al., Med. Klin. 87, pp. 378-384). , 1992) and thus represent antiarrhythmic drugs which are particularly suitable for the treatment of arrhythmic disorders which occur due to oxygen deficiency.

The compounds of the formula I according to the invention have a good cardioprotective action and are therefore particularly suitable for the treatment of infarction, for the prophylaxis of infarction and for the treatment of angina. In addition, the compounds of the formula I according to the invention are suitable for the treatment of all pathological hypoxic and ischemic lesions, so that they can be used for the treatment of primary and secondary diseases. The compounds of the formula I according to the invention are also suitable for preventive treatment.

Due to the protective action of the compounds of the formula I according to the invention in pathological, hypoxic or ischemic situations, further possibilities of use in surgical procedures for the protection of temporarily less-supplied organs, organ transplants to protect organs, angioplastic vascular or cardiac interventions, nerve ischemia system, in the treatment of shock conditions and preventive prevention of substantial hypertonia.

In addition, the compounds of the formula I according to the invention can be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, diabetic late complications, cancer, fibrotic diseases, particularly of the lung, liver and kidney, as well as hypertrophy and hyperplasia of organs. The substances moreover are suitable for diagnostic use for detection of diseases which are accompanied by increased activity of the Na ⁺ / H ⁺ antiporter, eg in erythrocytes, thrombocytes or leucocytes.

The action of the compounds of the invention can be determined by methods known per se, as described, for example, by N. Escobales and J. Figueroa (J. Membrane Biol, 120, 41-49, 1991) or by L. Counillon, W. Scholz, HJ Lang and J. Pouyssegur (Mol. Pharmacol. 44: 1041-1045, 1993).

Suitable experimental animals are, for example, mice, rats, guinea pigs, dogs, cats, monkeys or pigs.

The compounds of the formula I can therefore be used as active ingredients of medicaments in human and veterinary medicine. In addition, they can be used as intermediates for the manufacture of other drug active ingredients.

In formula (I), A represents a branched or unbranched alkyl group having 1 to 6 carbon atoms, preferably a group having 1 to 4 carbon atoms, and in particular a group having 1, 2 or 3 carbon atoms, such as preferably methyl, preferably ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).

R @ ¹ is preferably A, especially methyl or ethyl.

R @ ² and R @ ³ are preferably, independently of one another H, A, phenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-fluorophenyl or Het. Particularly preferably, one of the two symbols represents a hydrogen atom and the other represents the above-mentioned preferred group. The groups R ² and R ³ together may also together represent an alkylene group having 4 or 5 carbon atoms.

Ph is preferably unsubstituted phenyl or a phenyl group having one substituent selected from the group consisting of fluorine, chlorine and bromine, A, OA, amino, NHA, NA2 or trifluoromethyl.

Hal is fluorine, chlorine or bromine.

Het is preferably 2- or 3-furyl,

2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5 -oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or

5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or

4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1- , 3 or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or

5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2 or -5-yl, 1,2,4-thiadiazol-3- or 5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3- , 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-,

6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, δ-,

6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazyl, 2-, 3-,

4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7 or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9 -carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-,

6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic groups may also be partially or fully hydrogenated. For example, Het may also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl. , tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-,

-3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-,

-3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4- pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, - 3-, -4-, -5- or -δ-pyridyl, 1-, 2-, 3 or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4 -pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, - 6-,

-7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl group.

In general, all residues that occur several times in a compound, such as Het or Ph, may be the same or different from each other.

In particular, the invention relates to compounds of the formula I in which at least one of the abovementioned groups has at least one of the above-mentioned preferred meanings. Some preferred groups of compounds may be represented by the following formulas (Ia) to (Ih), which correspond to formula (I), wherein unspecified groups have the meanings given in formula (I), but wherein in formula (Ia) R ^{1 is} methyl or ethyl,

Ib R @ ^{1 is} methyl or ethyl and R @ ³ is hydrogen,

In Ic R ¹ is methyl or ethyl, R ³ is hydrogen and R ² is 2-thiazolyl,

In Id R ¹ is methyl or ethyl radical * R ³ is hydrogen, and R ² groups, or N-imidazolyl methylimidazolylovou,

R ^{1 is} methyl or ethyl, R ³ is hydrogen, and R ² is pyridyl or pyrimidinyl, R ^{1 is} methyl or ethyl, R ³ is hydrogen, and R ² is phenyl, fluorophenyl or chlorophenyl,

Ig R @ ¹ is methyl or ethyl, R ³ is hydrogen and R ² is alkyl having 1 to 6 carbon atoms,

In Ih R ¹ is methyl or ethyl, R ³ is hydrogen, and R ² group, piperidinyl or pyrrolidinyl, when R ¹ methyl, R ² and R ³ are independently alkyl having 1 to 6 carbon atoms, branched or unbranched.

Furthermore particularly preferred compounds which have preferred meanings of the substituents of formula Ia to Ih in which additionally means a group -SO2 methylsulfonyl and R ² is methyl or ethyl instead of hydrogen.

The process for the preparation of the ortho-substituted 4-aminobenzoylguanidine derivative of the formula I and its salts consists in reacting a compound of the formula II with guanidine

(II) wherein R2, ^R3 _and A have the abovementioned meanings and

A chlorine or bromine atom, an OA group, an O-CO-A group, an O-CO-Ph group, an OH group or another reactive hydroxyl esterified group or an easily nucleophilically replaceable release group, or a benzoylguanidine of the formula

(III) wherein ^RJ and A are as defined above and where is

R ⁴ is a fluorine, chlorine, bromine, iodine or other suitable release group, reacted with an amine or an amine derivative of formula IV R 3 -R ² -NH (IV) wherein R ² and R ³ are as defined above, or of the formula I, wherein the individual symbols have the meanings given above, but instead of one or more hydrogen atoms have one or more reducible groups and / or one or more additional CC- and / or CN bonds, are treated with a reducing agent or a compound of the formula I wherein the individual symbols have the meanings given above but, instead of having one or more hydrogen atoms, have one or more solvolysable groups, they are treated with a solvolysing agent and / or the base of the formula I obtained is converted by acid treatment into its salt.

The compounds of formula (I) are prepared by methods well known in the literature (for example, standard publications such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York). the aforementioned application) under the reaction conditions known and suitable for the said reactions. It is also possible to use variants which are known per se, not described here in greater detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but are immediately reacted further to the compounds of formula I.

Preferably, the compounds of formula (I) are prepared by reacting an activated carboxylic acid derivative of formula (II) wherein Q is particularly preferably chlorine or -O-CH3 with guanidine. Particularly suitable are reaction variants in which the free carboxylic acid of the formula II (Q represents a hydroxyl group) is reacted in a manner known per se to the corresponding activated derivative, which is then reacted directly with the guanidine without isolation. Methods in which intermediate insulation is dispensable are, for example, activation by carbonylimidazole, dicyclohexylcarbodiimide or the Mukayama variant (Angew. Chem. 91: 788-812, 1979).

The carboxylic acids of formula II are prepared, for example, by nucleophilic aromatic substitution from suitable benzoic acid derivatives with the corresponding amines. The reaction is carried out analogously to the reaction of the compounds of the formulas III and IV. This reaction will be described below.

The reaction of the reactive carboxylic acid derivative of the formula II with guanidine is carried out in a direct manner, preferably in a protic or aprotic polar or apolar inert organic solvent.

Suitable solvents for the reaction of compounds III and IV will be mentioned. However, particularly preferred solvents are methanol, tetrahydrofuran, dimethoxyethane, dioxane or mixtures thereof as well as water. The reaction temperature is, for example, 20 ° C to the boiling point of the solvent used. The reaction is carried out for 15 minutes to 12 hours. It is expedient to use acid-binding agents in the reaction. All bases which do not interfere with the reaction itself are suitable. However, inorganic bases such as potassium carbonate or organic bases such as triethylamine or pyridine are particularly suitable, or guanidine may be used in excess.

Further, the compounds of formula (I) may be prepared by reacting a benzoylguanidine of formula (III) with a compound of formula (IV), wherein each symbol is as defined above. The starting materials of the formula (III) can be prepared in a simple manner by reacting the appropriately substituted benzoic acid or reactive acid derivatives derived therefrom, for example from halides, esters or acid anhydrides, with guanidine under reaction conditions known per se and customary for amide preparation. Particularly suitable are those reaction variants which have been mentioned above for the reaction of the compounds of the formula II with guanidine.

The compounds of formula IV are as well known as their methods of preparation. If they are not known, they can be prepared by methods known per se.

The preparation of the compounds of the formula II as well as the reaction of the compounds of the formula III with the compound of the formula IV is carried out in a manner known per se, preferably in a protic or aprotic polar inert organic solvent.

According to a suitable variant, however, the reactants are reacted directly in the absence of a solvent.

In the preparation of compounds of formula II or in the reaction of compounds of formula III with compounds of formula IV, it is also expedient to work in the presence of a base or an excess of basic components. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, carbonates and alcoholates or organic bases such as triethylamine or pyridine, which can also be used in excess and then also act as a solvent.

Particularly suitable as inert solvents are alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as hexamethylphosphoric triamide; sulfoxides, such as dimethylsulfoxide (DMSO); chlorinated hydrocarbons, such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane, or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another may also be suitable.

Further, the compounds of formula I can be obtained by liberating from their functional derivatives solvolysis, in particular hydrolysis or hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the general formula I, but instead have one or more free amino and / or hydroxyl groups, corresponding protected amino and / or hydroxyl groups, preferably compounds which instead of a hydrogen atom which is bonded to a nitrogen atom, have an amino protecting group, especially compounds having an R'-N group instead of an NH group, where R 'is an amino protecting group, and / or compounds having a hydroxyl protecting group instead of a hydroxyl hydrogen atom, e.g. however, compounds which otherwise correspond to the general formula I have, instead of -OH, an -OR group, where R is a hydroxyl protecting group.

There may be several identical or different protected amino and / or hydroxyl groups in the molecule of the starting material. In many cases, where the protecting groups are different from one another, they may be selectively cleaved.

The term amino-protecting group is generally known and refers to groups which are suitable for protecting (to block) the amino group from chemical reactions, but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typically, such groups are unsubstituted or substituted acyl, aryl (e.g., 2,4-dinitrophenyl (DNP)), aralkoxymethyl (e.g., benzyloxymethyl (BOM)) or aralkyl (e.g., benzyl, 4-nitrobenzyl, triphenylmethyl) groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their species and bone command are not critical. However, groups having 1 to 20, and especially 1 to 8, carbon atoms are preferred. The term acyl is always meant in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or suiphonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butypyl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxy and cetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl; isopropoxycarbonyl; tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC) groups. Preferred amino protecting groups are BOC, DNP and BOM, CBZ, benzyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting (to block) the hydroxy group from chemical reactions, but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups as well as alkyl groups. Since the hydroxyl protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical. Preferred are, however, groups having 1 to 20, and especially 1 to 10, carbon atoms. Examples of hydroxyl protecting groups are tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the formula I used as starting materials can be prepared by methods known per se, which are known from the standard literature and the above-mentioned application, for example by reacting compounds of the general formulas II and III, but at least one of them it contains a protecting group instead of a hydrogen atom.

Depending on the protecting group used, the liberation of the compounds of the formula I from their functional derivatives is successful, for example with strong acids, preferably trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong carboxylic acids such as trichloroacetic acid or sulfonic acids. benzenesulfonic acid or toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.

Suitable inert solvents are organic, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be suitable. The trifluoroacetic acid is preferably used in excess without the addition of additional solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is expediently about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

For example, the BOC group may be preferably cleaved with 40% trifluoroacetic acid in dichloromethane or with about 3-5% hydrochloric acid in dioxane at a temperature of 15 to 60 ° C,

FMOC group with a 5 to 20% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at 15 to 50 ° C. Cleavage of the DNP group is also successful, for example, with an approximately 3 to 10% solution of 2-metaptoethanol in dimethylformamide / water at a temperature of 15 to 30 ° C.

Hydrogenolytically removable protecting groups (e.g. BOM, CBZ or benzyl groups) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of about 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. The hydrogenolysis of the CBZ group is successful, for example, on 5-10% palladium on carbon in methanol at 20-30 ° C.

The base of formula (I) can be converted into an appropriate acid addition salt by acid. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and ogranic acids may be used, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polyhydric carboxylic, sulfonic acids or sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, benzoic, salicylic, 2-phenylpropionic, or 3-phenylpropionic, citric, glonic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, and naphthalenedisulfonic and laurylsulfonic acids.

The compounds of the formula I and their physiologically acceptable salts can be used for the production of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active substances.

The invention therefore also relates to compositions, pharmaceutical compositions comprising at least one compound of formula I and / or a physiologically acceptable salt thereof.

These compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with the compounds of the formula I, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc, lanolin and your. Especially suitable for oral use are tablets, dragees, capsules, syrups, juices or drops, for rectal suppository use, for parenteral use solutions, especially oily or aqueous solutions, as well as suspensions, emulsions or implants, for topical use ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example, solutions in alcohols such as ethanol or isoproipanol, acetonitrile, dimethylformamide, dimethylacetamide, 1, 2-propanediol or mixtures thereof and / or with water) or powders. The compounds of the invention may also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injectables.

Particularly suitable for topical use are also posomal formulations. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or flavoring agents. If desired, they may contain one or more further active substances, such as vitamins.

The compounds of formula (I) and their physiologically acceptable salts can be administered to humans or animals, particularly mammals, such as monkeys, dogs, cats, rats or mice, and can be used for the therapeutic treatment of human or animal bodies therapy and / or prophylaxis of cardiovascular disorders. They are therefore suitable for the treatment of arrythmyms, especially if they are caused by oxygen deficiency, angina pectoris, infarction, ischemia of the nervous system such as stroke or brain swelling, shock conditions and preventive treatment.

Furthermore, the compounds of the formula I can be used as therapeutics in cases where cell proliferation is important, such as in arteriosclerosis, diabetic late complications, cancer, fibroses, as well as in organ hypertrophy and hyperplasia, particularly in the treatment of the prostate.

The compounds of the formula I according to the invention are generally employed in doses similar to known antirarhythmic drugs, for example aprindine, preferably at a dosage of about 0.01 to 5 mg, in particular 0.02 to 0.5 mg per dosage unit. The daily dose is about 0.0001 to 0.1 and particularly 0.0003 to 0.01 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, gender, cost, time and route of administration, excretion rate, drug combination, and disease severity . Oral administration is preferred.

The expression processing in the usual manner in the following examples illustrates:

Optionally, water is added, the reaction mixture is extracted with an organic solvent such as ethyl acetate, separating, drying the organic phase with sodium sulfate, filtering, evaporating and purifying by chromatography and / or crystallization.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 8.7 g of guanidine, dissolved in 60 ml of ethylene glycol dimethyl ether, was added dropwise at room temperature 6.6 g of 2-ethyl-4-piperidino-5-methylsulfonylbenzoic acid chloride (obtainable by reaction of 2-ethyl-4-chloro-5). -methylsulfonylbenzoic acid with excess piperidine followed by chlorination of SOCl 2) dissolved in 60 mL of ethylene glycol dimethyl ether and stirred for one hour at 25 ° C. The reaction mixture is mixed with 200 ml of ice water, acidified with 1N hydrochloric acid, extracted twice with 100 ml of ethyl acetate each time and the organic phase is discarded. The aqueous phase was basified with 1N sodium hydroxide solution and cooled. The precipitated product is suctioned off to give N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 218-220 ° C.

It is obtained analogously by reaction of guanidine with 2-methyl-4-pyrrolidino-5-methylsulphonylbenzoate.

of N-diaminomethylene-2-methyl-4-pyrrolidino-5-methylsulfonylbenzamide, m.p. 222-224 ° C, with 2-ethyl-4-pyrrolidino-5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4-pyrrolidino 5-methylsulfonylbenzamide, with chloride 2-methyl-4-N ', N'-dimethylamino-5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4-N', N'-dimethylamino-5-methylsulfonylbenzamide, with chloride 2-ethyl-4-Ν ', N'-diethylamino-5-methylsulphonylbenzoic acid N-diaminomethylene-2-ethyl-4-N', N'-diethylamino-5-methylsulphonylbenzamide, with 2-ethyl-4-Ν 'chloride N'-dimethylamino-5-methylsulphonylbenzoic acid N-diaminomethylene-2-ethyl-4-N ', N'-dimethylamino-5-methylsulphonylbenzamide, with 2-methyl-4-N', N'-diethylamine chloride n-5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4 ', N'-diethylamino-5-methylsulfonylbenzamide.

Example 2

Suspend 4 g of N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulphonylbenzamide (analogous to Example 1).

1) in 100 ml of water, dissolve with a stoichiometric amount of 1 molar aqueous hydrochloric acid solution and freeze-dry. There was thus obtained N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulfonylbenzamide in the form of the hydrochloride, m.p. &gt; 250 DEG C.

Similarly, it is obtained by treatment with aqueous hydrochloric acid and freeze-drying from N-diaminomethylene-2-methyl-4-pyrrolidino-5-methylsulfonylbenzamide N-diaminomethylene-2-methyl-4-pyrrolidino-5-methyisulfonylbenzamide hydrochloride, from N-diaminomethylene-2-ethyl1 4-pyrrolidino-5-methylsulfonylbenzamide, N-diaminomethylene-2-ethyl-4-pyrrolidino-5-methylsulfonylbenzamide hydrochloride, from N-diarainomethylene-2-methyl-4-phenylamino-5-methylsulfonylbenzamide N-diaminomethylene-2-methyl- 4-Phenylamino-5-methylsulfonylbenzamide hydrochloride, m.p.

Example 3

A solution of 20 g of 2-methyl-4-piperidino-5-methylsulphonylbenzoic acid methyl ester (obtainable by reaction of piperidine with 2-methyl-4-chloro-5-methylsulphonylbenzoic acid and subsequent esterification) and 30 g of guanidine which was liberated with sodium methylate from guanidine hydrochloride were stirred. 160 ml of methanol for 20 hours at 50 ° C. After cooling to 0 ° C, water is added, stirring is continued for one hour and the precipitate formed is filtered off with suction. Recrystallization from dichloromethane / methanol gave N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 222-224 ° C, the hydrochloride having a melting point of m.p.

275-276 CC.

Example 4

2.1 g of N-diaminomethylene-2-methyl-4-piperidino-5-methylsulphonylbenzamide (analogously to Example 4) are treated for 1 hour with a 1 molar aqueous hydrochloric acid solution and finally freeze-dried. N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide dihydrochloride of melting point 247 DEG C. is obtained.

Example 5

1 g of N-diaminomethylene-2-methyl-4-chloro-5-methylsulphonylbenzamide (obtainable by reaction of 2-methyl-4-chloro-5-methylsulphonylbenzoic acid chloride with guanidine according to Example 1) is maintained for 7 hours with stirring at 110 ° C. 1), 1 g of diisopropyl amine, 1 ml of sulfolane ^R and 0.55 g of potassium carbonate. 50 ml of ethyl acetate were added and the reaction mixture was extracted with 50 ml of 1N hydrochloric acid. The aqueous phase was adjusted to pH 12 with 1N sodium hydroxide solution and extracted twice with 100 ml of ethyl acetate. After working up in the usual manner and recrystallized from acetone, N-diaminomethylene-2-methyl-4- (4 ', N'-diisopropylamino) -5-methylsulphonylbenzamide is obtained.

Similarly, N-diaminomethylene-2-methyl-4- (N ', N'-dipropylamino) -5-methylsulfonylbenzamide is obtained by reacting N-diaminomethylene-2-methyl-4-chloro-5-methylsulfonylbenzamide with dipropylamine.

Example 6

Analogously to Example 1, N-diaminomethylene-2-methyl-4-phenylamino-5-methylsulfonylbenzamide, m.p. 202 DEG-207 DEG C., is obtained by reacting guanidine with 2-methyl-4-phenylamino-5-methylsulfonylbenzoic acid chloride, m.p. -methyl-4-N-methylanilino-5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4-N-methylanilino-5-methyl19-sulphonyl benzamide, with 2-methyl-4-diphenylamino-5-methylsulphonylbenzoic acid chloride N-diaminomethylene 2-methyl-4-diphenylamino-5-methylsulfonylbenzamide, with 2-ethyl-4-diphenylamino-5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4-diphenylamino-5-methylsulfonylbenzamide, with 2-methyl chloride -4- (2-chlorophenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (2-chlorophenylamino) 5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-2-chlorophenylamino) chloride - 5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (N-methyl-2-chlorophenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- chloride (3-chlorophenylamino) -5-methylsulfonylbenzoic acid, N-diaminomethylene-2-methyl-4- (3-chlorophenylamino) 5-methylsulfonylbenzamide, m.p. 19-319 ° C, melting point (methanesulfonate) 234-237 ° C with chloride 2-methyl-4- (N-methyl-3-chloroanilino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (N-methyl-3-chloroanilino) -5-methylsulfonylbenzamide, with 2-methyl-4- chloride (4-chlorophenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (4-chlorophenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-4-chloroanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (N-methyl-4-chloroanilino) -5-methylsulfonylbenzamide, with 2-methyl-4- (2-fluorophenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (2-Fluorophenylamino) -520 methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-2-fluoroanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (N-methyl-2-fluoroanilino) -5 -methylsulfones 1-benzamide, with 2-methyl-4- (3-fluorophenylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (3-fluorophenylamino) 5-methylsulfonylbenzamide, with 2-methyl-4- (N) chloride -methyl-3-fluoroanilino-5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4- (N-methyl-3-fluoroanilino) -5-methylsulphonylbenzamide, with 2-methyl-4- (4-fluorophenylamino) -5-chloride -methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (4-fluorophenylamino) 5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-4-fluoroanilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2 -methyl-4- (N-methyl-4-fluoroanilino) -5-methylsulfonylbenzamide, with 2-methyl-4- (2-methoxyphenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (2-methoxyphenylamide) 5-Methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-2-methoxyanilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (N-methyl-2- methoxyanilino) -5-methylsulfonylbenzamide, with 2-methyl-4-chloride - (3-methoxyphenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (3-methoxyphenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-3-methoxyanilino) chloride 5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (N-methyl-3-methoxyanilino) -5-methylsulfonylbenzamide, with 2-methyl-4- (4-methoxyphenylamino) -5-methylsulfonylbenzoic acid chloride, N- diaminomethylene-2-methyl-4- (4-methoxyphenyl amino) -5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-4-methoxyanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4 - (N-methyl-4-methoxyanilino) -5-methylsulfonylbenzamide, with 2-methyl-4- (2-cyanophenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (2-cyanphenylamino) -5 methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-2-cyananilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (N-methyl-2-cyananilino) -5-methylsulfonylbenzamide, with 2- methyl 4- (3-cyanophenylamino) -5-methyls N-diaminomethylene-2-methyl-4- (3-cyanophenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-3-cyananilino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl -4- (N-methyl-3-cyananilino) -5-methylsulfonylbenzamide, with 2-methyl-4- (4-cyanophenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (4-cyanphenylamino) -5 methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-4-cyanoanilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (N-methyl-4-cyananilino) -5-methylsulfonylbenzamide, with chloride 2 -methyl-4- (2-trifluoromethylphenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (2-trifluoromethylphenylamino) -5-methylsulfonylbenzamide, .....

with 2-methyl-4- (N-methyl-2-trifluoromethylanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (Nmethyl-2-trifluoromethylanilino) -5-methylsulfonylbenzamide, with 2-methyl chloride -4- (3-trifluoromethylphenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (3-trifluoromethylphenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (4-trifluoromethylphenylamino) -5- methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (4-trifluoromethylphenylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (N-methyl-4-trifluoromethylanilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2 methyl-4- (N-methyl-4-trifluoromethylanilino) -5-methylsulfonyl benzamide.

Similarly, it is obtained by reaction of N-diaminomethylene-2-ethyl-4-chloro

5-methylsulfonylbenzamide with 2-ethyl-4- (N ', N'-diisopropylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (N', N'-diisopropyl amino) -5-methylsulfonylbenz amide, with 2-ethyl-4- (N ', N'-dipropylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (N', N'-dipropylamino) -5-methylsulfonylbenzaraid, s 2-ethyl-4-phenylamino-5-methylsulphonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4-phenylamino-5-methylsulphonylbenzamide, with 2-ethyl-4-N-methylanilino-5-methylsulphonylbenzoic acid chloride N-diaminomethylene-2 -ethyl-4-N-methylanilino-5-methylsulphonylbenzamide, with 2-ethyl-4- (2-chlorophenylamino) -5-methylsulphonylbenzoic acid chloride, N-diaminomethylene-2-ethyl-4- (2-chlorophenylamino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (N-methyl-2-chloroanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (N-methyl-2-chloroanilino) -5-methylsulfonylbenzamide, with 2-ethyl- 4- (3-chlorophenylaraino) -5-methylsulfonylb enzoic acid N-diaminomethylene-2-ethyl-4- (3-chlorophenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-3-chloroanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl- 4- (N-methyl-3-chloroanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (4-chlorophenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (4-chlorophenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-4-chloroanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (N-methyl-4-chloroanilino) -5-methylsulfonylbenzamide, with chloride 2 -ethyl-4- (2-fluorophenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-ethyl-4- (2-fluorophenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-2-fluoroanilino) chloride 5-Methylsulfonylbenzoic acid N-diaminomethylene-2-ethyl-4- (N-methyl-2-fluoroanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (3-fluorophenylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene- 2-Ethyl-4- (3-fluorophenylamine) ino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-3-fluoroanilino) -5-methylsulfonyl-24-benzoic acid chloride, N-diaminomethylene-2-ethyl-4- (N-methyl-3-fluoroanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (4-fluorophenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (4-fluorophenylamino) -5 methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl- 4-fluoroanilino) -5-methylsulphonylbenzoic acid N-diaminomethylene-2-ethyl-4- (N-methyl-4-fluoroanilino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (2-methoxyphenylamino) -5-methylsulphonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (2-methoxyphenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-2-methoxyanilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-ethyl -4- (N-methyl-2-methoxyanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (3-methoxyphenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (3-methoxyphenylamino) - 5-methylsulfonylbenzamide, with chloride 2 -ethyl-4- (N-methyl-3-methoxyanilino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-ethyl-4- (N-methyl-3-methoxyanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- ( 4-methoxyphenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-ethyl-4- (4-methoxyphenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-4-methoxyanilino) -5-methylsulfonylbenzoic chloride N-diaminomethylene-2-ethyl-4- (N-methyl-4-methoxyanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (2-cyanophenylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-ethyl -4- (2-cyanophenylamino) -5-25 methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-2-cyanoanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- ( N-methyl-2-cyanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (3-cyanophenylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-ethyl-4- (3-cyanophenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-3-cyanoanilino) -5-methyl chloride N-diaminomethylene-2-ethyl-4- (N-methyl-3-cyananilino) -5-methylsulfonylbenzamide with 2-ethyl-4- (4-cyanophenylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2 -ethyl-4- (4-cyanophenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-4-cyananilino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-ethyl-4- (N-methyl- 4-Cyanoanilino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (2-trifluoromethylphenylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (2-1-trifluoromethylphenylamino) -5-methylsulfonylbenzaraid, s 2-ethyl-4- (N-methyl-2-trifluoromethylanilino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-ethyl-4- (N-ethyl-2-trifluoromethylanilino) -5-methylsulfonylbenzamide, with chloride 2 -ethyl-4- (3-trifluoromethyl-phenylamino) -5-methylsulphonylbenzoic acid N-diaminomethylene-2-ethyl-4- (3-trifluoromethylphenylamino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (4-trifluoromethylphenylamide) chloride (no) -5-me N-diaminomethylene-2-ethyl-4- (4-trifluoromethylphenylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (N-methyl-4-trifluoromethylanilino) -5-methylsulfonylbenzoic acid, N-diaminomethylene- 2-ethyl-4- (N-methyl-4-trifluoromethylanilino) -5-methylsulfonylbenzamide.

Example 7

Similar to Example 1, it is obtained by reacting guanidine with 2-methyl-4- (2-pyridylamino) -5-methylsulfonylbenzoic acid chloride (obtainable by reacting 2-methyl-4-fluoro-5-methylsulfonylbenzoic acid with 2-aminopyridine and then converting to guanidine). SOCl2) N-diaminomethylene-2-methyl-4- (2-pyridylamino) -5-methylsulfonylbenzamide, m.p. 225 DEG-226 DEG C., melting point methanesulfonate 235 DEG-237 DEG.

Similarly, it is obtained by reacting guanidine with 2-methyl-4- (3-pyridylamino) -5-methylsulphonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (3-pyridylamino) -5-methylphenylbenzamide, with 2- methyl 4- (3-pyridyl-N-methylamino) -5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4- (3-pyridyl-N-methylamino) -5-methylsulphonylbenzamide, with 2-methyl-4- (2-methyl chloride) -pyridyl-N-methylamino) -5-methylsulfonylbenzoic acid N-diaminoraethylene-2-methyl-4- (2-pyridyl-N-methylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (4-pyridylamino) -5- methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (4-pyridylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (4-pyridyl-N-methylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene 2-methyl-4- (4-pyridyl-N-methylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (2-pyrimidinylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (2-pyrimidinylamino) -5-methylsulfonylbenzamide, m.p. m.p. 247-248 ° C, methanesulfonate 243-245 ° C, with 2-methyl-4- (2-pyrimidinyl-N-methylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (2-pyrimidinyl) -N-methylamino) -5-methylsulfonylbenzamide, with 2-methyl-4- (1-methylimidazolyl-2-amino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (1-methylimidazolyl-2-amino) ) -5-methylsulfonylbenzamide, with 2-methyl-4- (1-methylimidazolyl-2-N-methylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (1-methylimidazolyl-2-N-methylamino) - 5-methylsulfonylbenzamide, with 2-methyl-4- (2-thiazolylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (2-thiazolylamino) 5-methylsulfonylbenzamide, with 2-methyl-4- ( 2-thiazolyl-N-methylamino) -5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4- (2-thiazolyl-N-methylamino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (2-pyridylamino) chloride -5-methylsulfonylbenzoic acid N-diaminomethylene- 2-methyl-4- (2-pyridylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (3-pyridylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (3-pyridylamino) - 5-methylsulfonylbenzamide, with 2-ethyl-4- (3-pyridyl-N-methylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- {3-pyridy128

N-methylamino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (2-pyridyl-N-methylamino) -5-methylsulphonylbenzoic acid chloride, N-diaminomethylene-2-methyl-4- (2-pyridyl) -N- methylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (4-pyridylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (4-pyridylamino) -5-methylsulfonylbenzamide, with chloride 2-ethyl-4- (4-pyridyl-N-methylamino) -5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4- (4-pyridyl-N-methylamino) -5-methylsulphonylbenzamide;

with 2-ethyl-4- (2-pyrimidinylamino) -5-methylsulfonylbenzoic acid chloride N-diaminomethylene-2-methyl-4- (2-pyrimidinylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (2-pyrimidinyl chloride) -N-methylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (2-pyrimidinyl-N-methylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (1-methylimidazolyl) chloride- amino-5-methylsulphonylbenzoic acid N-diaminomethylene-2-methyl-4- (1-methylimidazolyl-2-amino) -5-methylsulphonylbenzamide, with 2-ethyl-4- (1-methylimidazolyl-2-N) chloride -methylamino) -5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (1-methylimidazolyl-2-N-methylamino) -5-methylsulfonylbenzamide, with 2-ethyl-4- (2-thiazolylamino) chloride - 5-methylsulfonylbenzoic acid N-diaminomethylene-2-methyl-4- (2-thiazolylamino) 5-methylsulfonylbenzamide, with 2-ethyl-4- (2-thiazolyl-N-methylamino) -5-methylsulfonylbenzoic acid chloride, N-diaminomethylene-2 -methyl-4- (2-thiazolyl)

N-methylamino) -5-methylsulfonylbenzamide.

The following examples illustrate but do not limit the pharmaceutical compositions of the present invention:

Example A Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, filled into injection ampoules, lyophilized under sterile conditions and sealed . Each ampoule contains 5 mg of active substance.

Example B

Suppositories

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to solidify. Each suppository contains 20 mg of active ingredient.

Example C

Solution

A solution of 1 g of an active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to one liter and sterilized by irradiation. This solution can be used, for example, as eye drops.

Example D

Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of vaseline under aseptic conditions.

Example E

Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a manner known per se into tablets, each tablet containing 10 mg of the active ingredient Formula I.

Example F

Dragee

Similar to Example E, tablets are compressed and coated in a known manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G

Capsule

2 kg of active ingredient of the formula I are filled into hard gelatine capsules, each capsule containing 20 mg of active ingredient of the formula I.

Example H

Ampoule

A solution of 1 kg of active compound of the formula I in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed. Each ampoule contains 10 mg of the active substance.

Industrial applicability

The ortho-substituted 4-aminobenzoylguanidine derivative and its pharmaceutically acceptable salts have antiarrhythmic properties and are suitable for the preparation of pharmaceutical compositions which act as inhibitors of the cellular Na ⁺ / H ⁺ antiporter.

\ i

Claims (6)

PATENT CLAIMS. location Derivative 4-aminobenzoylguanidine of formula I OH3Λ * G '/ y o f- < > l! f) substituted, in (I) wherein is R ¹ by A, CF3, CH2F, CHF2 C2F5, R ² and R ³ are each independently hydrogen, A, C 3 -C 7 cycloalkyl, Ph or Het, or taken together with an alkylene group of 4 or 5 carbon atoms, Het a mononuclear or two-core, saturated, unsaturated or aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and / or sulfur atoms attached through a nitrogen or carbon atom, optionally substituted by one, two or three substituents selected from halogen, trifluoromethyl , A, hydroxy, OA, SH, SA, NH 2, NHA, NA 2, cyano, nitro and / or carbonyl oxygen, A (C1-C6) alkyl, Hal is fluorine, chlorine, bromine or iodine; A phenyl group optionally substituted by one, two or three substituents selected from the group consisting of A, OA, NH 2, NHA, NA 2, fluorine, chlorine, bromine and trifluoromethyl, and pharmaceutically acceptable salts thereof. The 4-aminobenzoylguanidine derivative substituted in ortho position according to claim 1, which is: (a) N-diaminomethylene-2-ethyl-4-piperidino-5-methylsulphonylbenzamide; (b) N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide; c) N-diaminomethyl, en-2-methyl-4-N, N-diisopropylamino-5-methylsulfonylbenzamide; d) N-diaminomethylene-2-methyl-4-phenylamino-5-methylsulfonylbenzamide; (e) N-diaminomethylene-2-methyl-4- (2-pyrimidinyl-amino) -5-methylsulfonylbenzamide; (f) N-diaminomethylene-2-methyl-4- (3-chlorophenylamino) -5-methylsulphonylbenzamide; g) N-diaminomethylene-2-methyl-4- (N ', N'-diisopropylamino-5-methylsulfonylbenzaraid), and pharmaceutically acceptable salts thereof. A process for the preparation of an ortho-substituted 4-aminobenzoylguanidine derivative of the formula I and its pharmaceutically acceptable salts according to claim 1, characterized in that a compound of the general formula II (II) wherein R ¹ , R 2 is reacted with guanidine ² , R3 _and A are as defined in claim 1 and wherein Q is chlorine or bromine, OA, O-CO-A, O-CO-Ph, OH or another reactive hydroxyl esterified group or a readily nucleophilically replaceable release group, or wherein R @ 4 and A are as defined in claim 1 and wherein R @ ⁴ is fluorine, chlorine, bromine, iodine or another suitable liberated group, is reacted with an amine or an amine derivative of formula IV R 3 R 2 NH (IV) wherein R ² and R ³ are as in Claim 1 hereinbefore defined, or a compound of formula I wherein the symbols are as defined above except that one or more hydrogen atoms contains one or more reducible groups and or one or more additional CC- and / or CN bonds, treated with a reducing agent, or a compound of formula I wherein the individual symbols are as defined above, but instead of one or more hydrogen atoms has one or more solvolysable groups, is treated with a solvolysing agent and / or converting the obtained base of the formula I by acid treatment into its salt. A pharmaceutical composition for combating diseases, in particular arrhythmic diseases, angina pectoris and infarction, and for the preventive treatment of these indications, characterized in that it comprises at least one 4-aminobenzoylguanidine derivative according to claim 1 and / or a physiologically acceptable salt thereof. Use of a 4-aminobenzoylguanidine derivative according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition. Use of a 4-aminobenzoylguanidine derivative according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of arrhythmias, angina pectoris, infarction and for the prophylactic treatment of these indications.